Sympathetic Neuropathy Linked To the Development of Myeloproliferative Neoplasms

Sympathetic Neuropathy Linked To the Development of Myeloproliferative Neoplasms

A new study published in the August 07, 2014 issue of Nature magazine reveals that an impaired neuro-endocrine microenvironment of the bone marrow plays a crucial role in the development and clinical outcome of myeloproliferative neoplasms (MPNs).

This and related studies may represent a breakthrough in hematology research and a paradigm shift in the MPNs’ therapeutic strategies. Interestingly, an increasing number of studies indicate that a dysfunctional brain-bone marrow communication may contribute to the pathogenesis of some common human diseases.

Innervation of bone marrow occurs late in fetal life, just before the onset of hemopoietic activity. Nerves enter the marrow accompanying arteries, travel with the vascular plexuses deep in the marrow, arborize in surrounding parenchyma, and end among hemato- and lymphopoietic cells. In the bone marrow, a close association between catecholamine-, glutamate-, or peptide-containing nerve fibers and osteoblasts or osteoclasts in the endosteum is often observed.

Circadian oscillations and the cyclical release of hematopoietic stem cells (HSCs) are regulated through circadian norepinephrine (noradrenaline) secretion by the sympathetic nervous system (SNS).

These noradrenergic signals, locally delivered by sympathetic nerves in the bone marrow are transmitted to stromal cells by the β3-adrenergic receptor (Méndez-Ferrer S et al., Nature, 2008; 452:442).

Recent evidence indicates that signals from the SNS modify the activity of the hematopoietic niche, acting as regulators of the mobilization of hematopoietic progenitors (Katayama Y et al., Cell, 2006, 124:407).

In the Nature study Lorena Arranz and colleagues from the Stem Cell Physiopathology Group at the Spanish National Cardiovascular Research Center, Madrid, Spain demonstrate that the neuroendocrine-immune mechanisms regulating the hematopoietic niche are impaired in MPN.

They provide evidence that in the bone marrow the overproduction of interleukin-1β by mutant progenitors can damage the Schwann cells that usually protect sympathetic nerve endings. This neuro‐glial damage enhances the susceptibility of mesenchymal stem cells (MSC) in the haematopoietic niche to cell death caused by mutant haematopoietic cells.

Thus, the authors report that the sympathetic nerve fibers, the supporting Schwann cells and MSCs are reduced in the bone marrow of MPN patients. Of note, administration of neuroprotective or sympathomimetic drugs such as β3-adrenergic agonists prevented mutant HSC expansion and MPN progression.

Currently, the only real cure available for MPN is a bone marrow transplant, which may not be advisable in some patients such as the elderly. This study may open the door to exploring a broader arsenal of therapeutic approaches in MPN.

Source: Nature, 2014 Aug 7;512(7512):78-81. doi: 10.1038/nature13383. Epub 2014 Jun 22.

Read More: Nature

Source: Cover Image: Bone anatomy. Author: Terese Winslow. Credit: National Cancer Institute, NIH, http://www.cancer.gov/cancertopics/pdq/treatment/mds-mpd/Patient/page1 Public domain.

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